Methoxyphenylethynyl, methoxypyridylethynyl and phenylethynyl derivatives of pyridine: Synthesis, radiolabeling and evaluation of new PET ligands for metabotropic glutamate subtype 5 receptors

Meixiang Yu, Werner Tueckmantel, Xukui Wang, Aijun Zhu, Alan P. Kozikowski, Anna Liisa Brownell

Research output: Contribution to journalArticle

Abstract

We have synthesized three different PET ligands to investigate the physiological function of metabotropic glutamate subtype 5 receptors (mGluR5) in vivo: 2-[11C]methyl-6-(2-phenylethynyl)pyridine ([ 11C]MPEP), 2-(2-(3-[11C]methoxyphenyl)ethynyl)pyridine ([11C]M-MPEP) and 2-(2-(5-[11C]methoxypyridin-3-yl) ethynyl)pyridine ([11C]M-PEPy). [11C]Methyl iodide was used to label the compounds under basic conditions, and a Pd(0) catalyst was applied to label [11C]MPEP in a Stille coupling reaction. In vivo microPET imaging studies of the functional accumulation of radiolabeled ligands were conducted in 35 rats (Sprague-Dawley, 8 weeks old male, weight of 300 g). Specific binding was tested using pre-administration of unlabeled mGluR5 antagonist 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) (10 mg/kg iv 5 min before radioactivity injection). In the radiolabeling of [11C]MPEP, [ 11C]M-MPEP and [11C]M-PEPy, a specific radioactivity of 700-1200 mCi/μmol and over 97% radiochemical purity were obtained. The microPET studies showed these three radiolabeled mGluR5 antagonists having the highest binding in the olfactory bulb followed by striatum, hippocampus and cortex. Pre-administration of the mGluR5 antagonist MPEP induced a 45.1% decrease in [11C]MPEP binding, a 59.7% decrease in [ 11C]M-MPEP binding and an 84.6% decrease in [11C]M-PEPy binding in the olfactory bulb at 5 min. The feasibility of synthesizing high-affinity and high-selectivity ligands for mGluR5 receptors and their suitability as PET imaging ligands for mGluR5 receptors in vivo are demonstrated.

Original languageEnglish (US)
Pages (from-to)631-640
Number of pages10
JournalNuclear Medicine and Biology
Volume32
Issue number6
DOIs
StatePublished - Aug 2005
Externally publishedYes

Fingerprint

Metabotropic Glutamate 5 Receptor
Ligands
Olfactory Bulb
Radioactivity
Sprague Dawley Rats
Hippocampus
Weights and Measures
Injections
pyridine

Keywords

  • Carbon-11
  • M-MPEP
  • M-PEPy
  • MgluR5
  • MPEP
  • PET

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

Methoxyphenylethynyl, methoxypyridylethynyl and phenylethynyl derivatives of pyridine : Synthesis, radiolabeling and evaluation of new PET ligands for metabotropic glutamate subtype 5 receptors. / Yu, Meixiang; Tueckmantel, Werner; Wang, Xukui; Zhu, Aijun; Kozikowski, Alan P.; Brownell, Anna Liisa.

In: Nuclear Medicine and Biology, Vol. 32, No. 6, 08.2005, p. 631-640.

Research output: Contribution to journalArticle

Yu, Meixiang ; Tueckmantel, Werner ; Wang, Xukui ; Zhu, Aijun ; Kozikowski, Alan P. ; Brownell, Anna Liisa. / Methoxyphenylethynyl, methoxypyridylethynyl and phenylethynyl derivatives of pyridine : Synthesis, radiolabeling and evaluation of new PET ligands for metabotropic glutamate subtype 5 receptors. In: Nuclear Medicine and Biology. 2005 ; Vol. 32, No. 6. pp. 631-640.
@article{a19f0707920149629b5e32d27a1e0cd3,
title = "Methoxyphenylethynyl, methoxypyridylethynyl and phenylethynyl derivatives of pyridine: Synthesis, radiolabeling and evaluation of new PET ligands for metabotropic glutamate subtype 5 receptors",
abstract = "We have synthesized three different PET ligands to investigate the physiological function of metabotropic glutamate subtype 5 receptors (mGluR5) in vivo: 2-[11C]methyl-6-(2-phenylethynyl)pyridine ([ 11C]MPEP), 2-(2-(3-[11C]methoxyphenyl)ethynyl)pyridine ([11C]M-MPEP) and 2-(2-(5-[11C]methoxypyridin-3-yl) ethynyl)pyridine ([11C]M-PEPy). [11C]Methyl iodide was used to label the compounds under basic conditions, and a Pd(0) catalyst was applied to label [11C]MPEP in a Stille coupling reaction. In vivo microPET imaging studies of the functional accumulation of radiolabeled ligands were conducted in 35 rats (Sprague-Dawley, 8 weeks old male, weight of 300 g). Specific binding was tested using pre-administration of unlabeled mGluR5 antagonist 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) (10 mg/kg iv 5 min before radioactivity injection). In the radiolabeling of [11C]MPEP, [ 11C]M-MPEP and [11C]M-PEPy, a specific radioactivity of 700-1200 mCi/μmol and over 97{\%} radiochemical purity were obtained. The microPET studies showed these three radiolabeled mGluR5 antagonists having the highest binding in the olfactory bulb followed by striatum, hippocampus and cortex. Pre-administration of the mGluR5 antagonist MPEP induced a 45.1{\%} decrease in [11C]MPEP binding, a 59.7{\%} decrease in [ 11C]M-MPEP binding and an 84.6{\%} decrease in [11C]M-PEPy binding in the olfactory bulb at 5 min. The feasibility of synthesizing high-affinity and high-selectivity ligands for mGluR5 receptors and their suitability as PET imaging ligands for mGluR5 receptors in vivo are demonstrated.",
keywords = "Carbon-11, M-MPEP, M-PEPy, MgluR5, MPEP, PET",
author = "Meixiang Yu and Werner Tueckmantel and Xukui Wang and Aijun Zhu and Kozikowski, {Alan P.} and Brownell, {Anna Liisa}",
year = "2005",
month = "8",
doi = "10.1016/j.nucmedbio.2005.05.004",
language = "English (US)",
volume = "32",
pages = "631--640",
journal = "Nuclear Medicine and Biology",
issn = "0969-8051",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Methoxyphenylethynyl, methoxypyridylethynyl and phenylethynyl derivatives of pyridine

T2 - Synthesis, radiolabeling and evaluation of new PET ligands for metabotropic glutamate subtype 5 receptors

AU - Yu, Meixiang

AU - Tueckmantel, Werner

AU - Wang, Xukui

AU - Zhu, Aijun

AU - Kozikowski, Alan P.

AU - Brownell, Anna Liisa

PY - 2005/8

Y1 - 2005/8

N2 - We have synthesized three different PET ligands to investigate the physiological function of metabotropic glutamate subtype 5 receptors (mGluR5) in vivo: 2-[11C]methyl-6-(2-phenylethynyl)pyridine ([ 11C]MPEP), 2-(2-(3-[11C]methoxyphenyl)ethynyl)pyridine ([11C]M-MPEP) and 2-(2-(5-[11C]methoxypyridin-3-yl) ethynyl)pyridine ([11C]M-PEPy). [11C]Methyl iodide was used to label the compounds under basic conditions, and a Pd(0) catalyst was applied to label [11C]MPEP in a Stille coupling reaction. In vivo microPET imaging studies of the functional accumulation of radiolabeled ligands were conducted in 35 rats (Sprague-Dawley, 8 weeks old male, weight of 300 g). Specific binding was tested using pre-administration of unlabeled mGluR5 antagonist 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) (10 mg/kg iv 5 min before radioactivity injection). In the radiolabeling of [11C]MPEP, [ 11C]M-MPEP and [11C]M-PEPy, a specific radioactivity of 700-1200 mCi/μmol and over 97% radiochemical purity were obtained. The microPET studies showed these three radiolabeled mGluR5 antagonists having the highest binding in the olfactory bulb followed by striatum, hippocampus and cortex. Pre-administration of the mGluR5 antagonist MPEP induced a 45.1% decrease in [11C]MPEP binding, a 59.7% decrease in [ 11C]M-MPEP binding and an 84.6% decrease in [11C]M-PEPy binding in the olfactory bulb at 5 min. The feasibility of synthesizing high-affinity and high-selectivity ligands for mGluR5 receptors and their suitability as PET imaging ligands for mGluR5 receptors in vivo are demonstrated.

AB - We have synthesized three different PET ligands to investigate the physiological function of metabotropic glutamate subtype 5 receptors (mGluR5) in vivo: 2-[11C]methyl-6-(2-phenylethynyl)pyridine ([ 11C]MPEP), 2-(2-(3-[11C]methoxyphenyl)ethynyl)pyridine ([11C]M-MPEP) and 2-(2-(5-[11C]methoxypyridin-3-yl) ethynyl)pyridine ([11C]M-PEPy). [11C]Methyl iodide was used to label the compounds under basic conditions, and a Pd(0) catalyst was applied to label [11C]MPEP in a Stille coupling reaction. In vivo microPET imaging studies of the functional accumulation of radiolabeled ligands were conducted in 35 rats (Sprague-Dawley, 8 weeks old male, weight of 300 g). Specific binding was tested using pre-administration of unlabeled mGluR5 antagonist 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) (10 mg/kg iv 5 min before radioactivity injection). In the radiolabeling of [11C]MPEP, [ 11C]M-MPEP and [11C]M-PEPy, a specific radioactivity of 700-1200 mCi/μmol and over 97% radiochemical purity were obtained. The microPET studies showed these three radiolabeled mGluR5 antagonists having the highest binding in the olfactory bulb followed by striatum, hippocampus and cortex. Pre-administration of the mGluR5 antagonist MPEP induced a 45.1% decrease in [11C]MPEP binding, a 59.7% decrease in [ 11C]M-MPEP binding and an 84.6% decrease in [11C]M-PEPy binding in the olfactory bulb at 5 min. The feasibility of synthesizing high-affinity and high-selectivity ligands for mGluR5 receptors and their suitability as PET imaging ligands for mGluR5 receptors in vivo are demonstrated.

KW - Carbon-11

KW - M-MPEP

KW - M-PEPy

KW - MgluR5

KW - MPEP

KW - PET

UR - http://www.scopus.com/inward/record.url?scp=22144488055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=22144488055&partnerID=8YFLogxK

U2 - 10.1016/j.nucmedbio.2005.05.004

DO - 10.1016/j.nucmedbio.2005.05.004

M3 - Article

C2 - 16026710

AN - SCOPUS:22144488055

VL - 32

SP - 631

EP - 640

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

SN - 0969-8051

IS - 6

ER -